PTR-037-1

(Supersedes PTR-037)
Hydrodynamic Robustness of Hypromellose and
Hydroxypropyl Cellulose Based Modified
Release Matrix Systems
by
D. Tewari, R.K. Lewis, W.W. Harcum, T. Drig
Abstract Summary
Factors impacting the hydrodynamic robustness of hypromellose and hydroxypropylcellulose matrix
systems were investigated using the USP III reciprocating apparatus. Drug release from systems with low
(10%) polymer level, low drug solubility or erosion dependent release mechanisms were generally found to
vary significantly with change in hydrodynamics.
Introduction
Recent studies indicate that the USP I (basket) and USP II (paddle) apparatus are often poorly predic-
tive of in vivo release profiles, especially during the fed state, when a dosage form may be retained for 4-6
hours in the stomach, while continuously subjected to 3 to 4 contractions per minute. In contrast, the
unconventional method of testing the modified release matrix tablets in the more hydrodynamically aggres-
sive USP disintegration test was highly predictive of in vivo behavior (1). Hypromellose (HPMC) and
hydroxypropyl cellulose (HPC) are widely used hydrophilic matrix polymers, however most published data
on systems utilizing these two polymers is based on the conventional USP I or II dissolution apparatus. The
current study aims to evaluate hydrodynamic robustness of HPMC and HPC matrix systems, taking poly-
mer level, polymer molecular weight (MW) and drug solubility into account. As the disintegration test is
not well suited for precise drug release studies on individual tablets, we chose the closely related USP III
reciprocating cylinder dissolution apparatus. A variety of hydrodynamic conditions including the high
shear, high fluid flow conditions of the disintegration test (as a model of fed state hydrodynamic condi-
tions) as well as lower shear environments, more reflective of fasted state and intestinal hydrodynamic con-
ditions were simulated by varying the reciprocation rate at 5, 15 and 25 dips per minute (dpm). Dissolution
behavior in USP Apparatus I (basket) at 100 RPM was used as the reference and compared to USP
Apparatus III at 5, 15 and 25 dips per minute (DPM), using the f
2
similarity factor. Profiles with f
2
values
>50 are generally regarded as similar.
(over)
Hercules Incorporated
Aqualon Division
Hercules Plaza
1313 North Market Street
Wilmington, DE 19894-0001
(800) 345-0447
www.aqualon.com
Pharmaceutical Technology Report
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PTR-037-1
Page 2 of 8
Experimental Methods
Table 1 lists the HPMC Type 2208 and HPC grades studied. Each polymer type was studied at two
MW levels spanning intermediate (300-370 kDA) to high MW (1000-1300 kDA). Polymer loading was 10
and 30%. The model drugs were soluble theophylline (THEO, solubility 6.9mg/ml in pH 6.8 buffer at
37C) and low soluble glipizide (GLIP, solubility 1.8 mg/ ml at pH 7.5 with 0.5% polysorbate 80 at 37C).
400 mg Tablets comprising 25% drug (THEO or GLIP), 30% or 10% polymer (2 polymers at 2 molecular
weights each), 0.5% magnesium stearate and q.s. microcrystalline cellulose were prepared by compression
on a instrumented rotary tablet press. Hydrodynamic robustness was assessed based on similarity of disso-
lution profiles under different conditions, lack of erratic release patterns and low variability as measured by
maximum standard deviation at individual dissolution time points.
Table 1. Aqualon Pharmaceutical Grade Cellulose Ether Polymers used in this Study.
Viscosity* Nominal MW
Grade (mPa.s) (kDa)
Benecel

HPMC K4M PH CR 32000-48000 at 2% 340

Benecel HPMC K100M PH CR 3300-5200 at 2% 1000
Klucel

HPC GXF 150-400 at 2% 370

Klucel HPC HXF 1500-3000 at 1% 1150
*Viscosity measured according to USP Monograph
Results and Discussion
General Observations: Factors which predispose a system toward diffusional release and minimize
erosional contributions increase the likelihood of achieving a hydrodynamically robust system. These fac-
tors include high drug solubility and high gel strength, which can be achieved through increasing polymer
MW and polymer loading. In contrast, lower MW and lower polymer loadings and lower drug solubility
increase the erosional contributions to total drug release, leading to greater hydrodynamic sensitivity.
Soluble Drug Dissolution, 30% Polymer Level: For soluble THEO, the USP I basket apparatus dissolu-
tion conditions at 100 rpm were generally similar to the USP III reciprocating cylinder apparatus at 5 dpm.
Due to superior gel strength, formulations with 30% high MW HPC and HPMC were the most hydro-
dynamically robust, with no significant dissolution effect even at 25 dpm (Table 2 and Figures 1 and 2). In
these systems drug is primarily released via diffusion through the hydrated gel matrix with negligible
matrix erosion. High MW HPC had the longest release duration (t
60
% 14-15 hours). For high MW HPMC
the t
60
% values varied form 9-11 hours depending on hydrodynamic conditions. Similarly, THEO formula-
tions comprising 30% medium MW HPC or HPMC were hydro-dynamically robust up to 15 dpm, but
release profiles accelerated markedly under extreme shear conditions of 25 dpm (f
2
values <50). Figures 3
and 4 illustrate the dissolution behavior of Medium MW HPC and HPMC systems.
Soluble Drug Dissolution, 10% Polymer Level: At low polymer levels, high MW HPC is not as effec-
tive as HPMC with t
60
% ranging from 3.5-4 hours as opposed to 5-6 hours for HPMC (Table 2 and Figures
1 and 2. At the 10% polymer level the variability of individual tablets increases markedly as hydrodynamic
stress increases (Table 3). Low polymer loadings were also problematic for THEO formulations comprising
intermediate MW polymer grades. Medium MW HPC was ineffective (t
60
% <1.5 hours under all dissolu-
tion conditions). For medium MW HPMC release times were longer, but extreme hydrodynamic sensitivity
even at the lowest reciprocating cylinder frequency of 5 dpm was seen. (Table 3 and Figures 3 and 4).
Based on these findings, 10% polymer levels should generally be avoided for soluble drugs.
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Page 3 of 8
Insoluble Drug Dissolution, 30% level: With the exception of high MW HPC and HPMC at 30%,
insoluble GLIP formulations were not as hydrodynamically robust as THEO formulations. However high
MW HPMC and HPC at 30% are of limited use due to the physiologically unrealistically long dissolution
times (t
60
%>>24 hours, Table 2). This can be attributed to the fact that erosion is required for GLIP release
as diffusion alone is limited by low drug solubility. Medium MW HPC profiles were linear and had low
variability under a specific hydrodynamic condition (Figure 5). This was not the case for medium MW
HPMC which was more variable and erratic (Figure 6 and Table 3).
Insoluble Drug Dissolution, 10% level: High MW HPC GLIP tablets were extremely sensitive to
hydrodynamic changes even when switching from USP Apparatus I to USP Apparatus III at 5 dpm. (f
2
= 39).
10% High MW HPMC was robust at 5 dpm, but release and variability in individual tablets markedly
increased at 15 and 25 dpm. Medium MW HPC was ineffective at 10% polymer levels with t
60
% ranging
from 0.25 to 1 hour ( Tables 2 and 3 and Figures 5 and 6).
Conclusion
Our study shows that low (10%) polymer levels were generally problematic for both soluble and insolu-
ble drugs, resulting variably in insufficient release retardation, high variability or poor hydrodynamic robust-
ness. At 30% polymer levels, hydrodynamically robust matrix tablets can be achieved for soluble drugs.
However it was not possible to achieve hydrodynamic robustness beyond 5 dpm for low soluble, erosion
dependent drug matrix systems, while simultaneously achieving release durations less than 24 hours.
It is important to select dissolution conditions that provide physiologically relevant levels of shear,
especially with respect to fed state conditions. The USP apparatus III set at 15 dpm appears highly suitable
for this purpose.
References
1. International Patent Application, WO 03/035029 A1. Louie-Helm, J. and Berner, B. May 2003.
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PTR-037-1
Page 4 of 8
Table 2. Matrix Polymer, Polymer level and Hydrodynamic Effects on Drug Dissolution
T
60
% (Hrs) f
2
Value (USP I,
MW Polymer USP 1 100 RPM as Reference)
Type, Level 100 RPM 5 DPM 15 DPM 25 DPM 5 DPM 15 DPM 25 DPM
Theophylline
High HPMC, 30% 13 10 11 9 63 66 53
HPMC, 10% 4 6 6 5 62 66 74
HPC, 30% 19 15.5 15.5 14 77 71 59
HPC, 10% 4 3.5 4 3.5 87 74 80
Medium HPMC, 30% 10 9 7.5 6 72 54 42
HPMC, 10% 3 6 6 3.5 42 41 71
HPC, 30% 8 8 8 6 83 81 40
HPC, 10% 1.5 1 0.50 0.50 59 41 38
Glipizide
High HPMC, 30% >24 >24 >24 >24 66 86 56
HPMC, 10% 24 19 12 9 60 34 32
HPC, 30% >24 >24 >24 >24 67 78 79
HPC, 10% >24 15.5 9 9 40 26 26
Medium
HPMC, 30% >24 >24 16 17 79 43 41
HPMC, 10% 19 18.5 14 9 85 60 40
HPC, 30% 17.5 14.5 10 9 65 40 34
HPC, 10% 0.75 0.8 <0.25 <0.25 42 22 27
*f
2
value in red indicate failure of the dissolution.
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Table 3. Matrix Polymer, Polymer Level and Hydrodynamic Effects on Variability of Individual Time Points
Polymer
Type, Level USP 1 Maximum Standard Deviation
MW 100 RPM 5 DPM 15 DPM 25 DPM
Theophylline
High HPMC 30% 0.24 1.47 0.82 0.70
HPMC 10% 4.12 1.35 4.12 6.48
HPC 30% 1.44 1.38 0.57 0.39
HPC 10% 0.5 1.71 5.23 3.21
Medium HPMC 30% 1.86 1.10 3.17 2.31
HPMC 10% 7.15 2.82 1.59 4.20
HPC 30% 1.19 1.45 3.17 0.92
HPC 10% 3.63 2.46 6.04 1.73
Glipizide
High HPMC 30% 3 0.93 2.66 3.03
HPMC 10% 2.95 4.00 1.63 4.25
HPC 30% 0.5 0.27 1.44 1.39
HPC 10% 1.0 2.26 4.34 2.78
Medium HPMC 30% 1.7 1.90 0.86 6.94
HPMC 10% 3.47 3.60 3.70 5.65
HPC 30% 4.76 7.81 0.84 2.90
HPC 10% 3.47 2.13 0.51 0.5
*S.D values in red indicate high standard deviation.
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PTR-037-1
Page 6 of 8
Figure 1. Effect of high MW HPC levels and hydrodynamics on release from soluble theophylline matrix tablets.
0
20
40
60
80
100
0 5 10 15 20 25
Time (Hours)
10%
30%
% Theophylline Dissolved
USP I, 100 RPM
USP III, 5 DPM
USP III, 15 DPM
USP III, 25 DPM
Figure 2. Effect of high MW HPMC Type 2208 levels and hydrodynamics on release from soluble
theophylline matrix tablets.
0
20
40
60
80
100
0 5 10 15 20 25
Time (Hours)
10%
30%
% Theophylline Dissolved
USP I, 100 RPM
USP III, 5 DPM
USP III, 15 DPM
USP III, 25 DPM
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Page 7 of 8
Figure 3. Effect of medium MW HPC levels and hydrodynamics on release from soluble theophylline
matrix tablets.
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0
20
40
60
80
100
0 5 10 15 20 25
Time (Hours)
10%
30%
% Theophylline Dissolved
USP I, 100 RPM
USP III, 5 DPM
USP III, 15 DPM
USP III, 25 DPM
Figure 4. Effect of medium MW HPMC levels and hydrodynamics on release from soluble theophylline
matrix tablets.
0
20
40
60
80
100
0 5 10 15 20 25
Time (Hours)
10%
30%
% Theophylline Dissolved
USP I, 100 RPM
USP III, 5 DPM
USP III, 15 DPM
USP III, 25 DPM
PTR-037-1
Page 8 of 8
Figure 5. Effect of medium MW HPC levels and hydrodynamics on release from insoluble glipizide matrix tablets.
0
20
40
60
80
100
0 5 10 15 20 25
Time (Hours)
30%
10%
% Glipizide Dissolved
USP I, 100 RPM
USP III, 5 DPM
USP III, 15 DPM
USP III, 25 DPM
Figure 6. Effect of medium MW HPMC levels and hydrodynamics on release from insoluble glipizide
matrix tablets.
0
20
40
60
80
100
0 5 10 15 20 25
Time (Hours)
30%
10%
% Glipizide Dissolved
USP I, 100 RPM
USP III, 5 DPM
USP III, 15 DPM
USP III, 25 DPM
9-07
Hercules Incorporated, 2007